IL41259A - 3-((4-methyl-1-piperazinyl carbonyl)oxy)-2-(2-quinolyl)-1-isoindoline derivatives,process for their preparation and pharmaceutical compositions containing the same - Google Patents

3-((4-methyl-1-piperazinyl carbonyl)oxy)-2-(2-quinolyl)-1-isoindoline derivatives,process for their preparation and pharmaceutical compositions containing the same

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IL41259A
IL41259A IL41259A IL4125973A IL41259A IL 41259 A IL41259 A IL 41259A IL 41259 A IL41259 A IL 41259A IL 4125973 A IL4125973 A IL 4125973A IL 41259 A IL41259 A IL 41259A
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isoindoline
general formula
isoindolin
preparation
derivatives
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IL41259A
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Rhone Poulenc Sa
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Priority claimed from FR7200650A external-priority patent/FR2167217A1/en
Priority claimed from FR7241272A external-priority patent/FR2206936A2/en
Application filed by Rhone Poulenc Sa filed Critical Rhone Poulenc Sa
Publication of IL41259A0 publication Critical patent/IL41259A0/en
Publication of IL41259A publication Critical patent/IL41259A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03G—ELECTROGRAPHY; ELECTROPHOTOGRAPHY; MAGNETOGRAPHY
    • G03G15/00—Apparatus for electrographic processes using a charge pattern
    • G03G15/14—Apparatus for electrographic processes using a charge pattern for transferring a pattern to a second base
    • G03G15/16—Apparatus for electrographic processes using a charge pattern for transferring a pattern to a second base of a toner pattern, e.g. a powder pattern, e.g. magnetic transfer

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  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Indole Compounds (AREA)

Description

3-[ (4-methyl-l-piperazinyl carbonyl) oxy] -2- (2-quinolyl) -1-isoindoline derivatives, process for their preparation and pharmaceutical compositions containing the same -[»opiK(V>3im 3 "^ns's-l -V»na-4)j -3 nnVin naDn*? T^nn , 1 ^n. »NI t »κ-1 -(Y***? 1 :n¾p-2)-2 iniK m^'Dan ninpn nunyni This Invention relates to BOW therapeutically useful Isoindoline derivatives, to processes for their preparation and pharmaceutical compositions containing them.
The new isoindoline derivatives of the present invention are those of the general formula* wherein represents a hydrogen, or halogen atoo, an alkyl or alkoxy radical containing 1 to 4 carbon atoae or a nitro radical and n represents sero or 1 , and add addition salts thereof.
In Israel patent specification 37547 and 39337 there are described isolndolinone derivatives having therapeutic properties, however the compounds of the present invention differ In structure and also show superior pharmacological properties when coiapared with the compounds disclosed in said patents.
According to a feature of the invention, the isoindoline derivatives of geneal formula I wherein & represents aero are prepared by the process which comprises reacting 1 • iblorocari»nyl^«^thylpiperaaine with an alkali oetal salt, optionally prepared situ, of an Isoindoline derivative of the eneral formulas wherein the various symbols are as hereinbefore defined. The reaction is generally carried out in an anhydrous organic solvent, for example diraethylformaniide, at a temperature below 50°C. , preferably at 10--35°C, The isoindollne derivatives of general formula II can be obtained by the partial reduction of a phthalimlde derivative of the general formula. wherein the various symbols are as hereinbefore de ined. The reduction is generally carried out by means of an alkali metal borohydride in an organic (e.g. an alcohol) or an aqueous-organic (e.g. an aqueous alcohol or aqueous dioxan) solution.
When the phthalimido radical Is unsymmetrically substituted, the partial reduction of a compound of general formula XII can lead to isomeric products which can be separated by physico-chemical methods such as fractional crystallisation or chromatography.
The phthalimlde derivatives of general formula III can be obtained by reaction of an aminoquinoline of the general formula: (wherein Y is as hereinbefore defined) with a phthalic anhydride of the general formula: According to a further feature of the invention, the isoindoline derivatives of general formula I wherein n represents zero are prepared by the process which comprises reacting 1-methylpipexazine with a mixed carbonate of the general formula: wherein Y is as hereinbefore defined, and Ar represents a phenyl radical optionally substituted by, for example, an alkyl radical containing 1 to 4 carbon atoms. The reaction is generally carried out in an organic solvent, for example acetonitrile , and at a temperature between 10° and 35°C.
The mixed carbonates of general formula VI can be prepared by reaction of a chloroformate of the general formula: Cl-CO-O-Ar VII (wherein Ar is as hereinbefore defined) with an isoindoline derivative of general formula II. The reaction is generally carried out in a basic organic solvent, for example pyridine, and at a temperature below or near ambient temperature, e.g. from 5° to 200c„ According to another feature of the invention, the isoindoline derivativesof general formula I wherein n represents 1 are prepared by the process which comprises oxidising a corresponding compound of general formula I, wherein rj, is zero, by methods known per se for the N-oxidation of the piperazine nucleus. The oxidation is generally carried out by means of a peracid, for example p-nitroperbenzoic acid, in an organic solvent, for example chloroform, and at a temperature of about 20°C.
'The isoindoline derivatives of general formula I obtained by the aforementioned processes can be purified by physical methods such as distillation, crystallisation or chromatography, or by chemical methods such as the formation of salts, crystallisation of the salts and decomposition of them in an alkaline medium. In carrying out the said chemical methods the nature of the anion of the salt is immaterial, the only requirement being that the salt must be well-defined and readily crystallisable.
The isoindoline derivatives of general formula I may be converted by methods known per se into acid addition salts. The acid addition salts may be obtained by the action of acids on the isoindoline derivatives in appropriate solvents. As organic solvents there may be used alcohols, ethers, ketones or chlorinated hydrocarbons. ΉΊΘ salt which is formed is precipitated, if necessary after concentration of the solution, and is isolated by filtration or decantation.
By the term "methods known per se" as used in this specification is meant methods heretofore used or described in the chemical literature. Ί¾β isoindoline derivatives of the invention and their acid addition salts possess valuable pharmacological properties; they are particularly active as ranquilisere and anti-convulsant agents.
In animals (mice) they have proved active as such at doses of between 10 and 100 mg./kg. animal body weight when administered orally, in particular in the following tests: (i) electric battle test according to a technique similar to that of Tedeschi et al [j. Pharmacol. , 125 , 28 (1959)], (ii) convulsion with pentetrazole according to a technique similar to that of Everett and Richards [j. Pharmacol., 81, 402 (1944)], (iii) supramaximal electroshock according to the technique of Swinyard et al [j. Pharmacol., 106,319 (1952)], and (iv) locomotor activity according to the technique of Courvoisier [Congres de e'decins Alienietes et Neurologistes - lours - (8/13th June, 1959)] and Julou (Bulletin de la SociSt6 de Pharmaoie de Lille, No. 2, January 1967, page 7).
Preferred isoindoline derivatives of the invention are those of general formula X wherein Y represents a halogen (preferably chlorine) atom, or an alkyl (preferably methyl) or alkoxy (preferably methoxy) radical containing 1 to 4 carbon atoms, or a nitro group, and especially those in which the quinolyl radical is attached through the 2-position to the isoindoline nucleus, and their acid addition salts. Of outstanding importance is 3- (4-methyl-piperaain-l-yl)carbonyloxy-2- (7-chloroguinol-2-yl)-isoindolin-l-one.
For therapeutic purposes/the isoindoline derivatives of ^general formula I may be employed as such or in the form of non-toxic acid addition salts, i.e. salts containing anions which are relatively innocuous to the animal organism in therapeutic doses of the salts (such as hydrochlorides, sulphates, nitrates, phosphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, theophyllinacetates, salicylates, phenolphthalinates and methylene-bis-B-hydroxynaphthoates) so that the beneficial physiological properties inherent in the bases are not vitiated by side effects ascribable to the anions.
The following Examples illustrate the invention.
Example 1 A solution of 3-hydroxy-2-(quinol-2-yl)-isonidoline- , 1-one (7 g.) in anhydrous dimethylformamide (90 cc.) is added to a suspension of sodium hydride (50% dispersion in mineral oil) (1.35 g.) in anhydrous dimethylformamide (65 cc. ) , whilst keeping the temperature at about 20°C. When the evolution of gas is complete a solution of l-chlorocarbonyl-4-methylpiperazine (4.6 g. ) in anhydrous dimethylformamide (16 cc.) is added. The reaction mixture is stirred for a further 2 hours after the end of the addition and is then poured into ice-water (1,000 cc). The product which crystallises is filtered off and then washed with water (150 cc. ) .
After drying, a product (10 g. ) , which melts at 155°C. , is obtained. On recrystallisation from diisopropyl ether (1 ,150 cc. ) , 3-(4-methylpiperazin-l-yl ) carbonyloxy-2-(quinol-2-yl)isoindolin-l-one (7 g. ) , which melts at 160°C. , is obtained. 3-Hydroxy-2-(quinol-2-yl) isoindolin-l-one can be prepared by adding potassium borohydride (2.2 g. ) to a suspension of 2-phthalimidoquinoline (13.6 g. ) in methanol (500 cc.), whilst stirring and keeping the temperature at about 15°C. After stirring for one hour at a temperature of about 20°G. , the insoluble product is filtered off and then washed with methanol (25 cc. ).
After drying, a product (11.3 g. ) , which melts at 172°C. , is obtained and is dissolved in methylene chloride (400 cc. ), After removing a slignt amount of insoluble material, the solution obtained is filtered through silica gel (200 g. ) contained in a column 4.2 cm. in diameter. Elution is then carried out with methylene chloride (1,000 cc. ).
This eluate is discarded. Further elution is carried out with methylene chloride (6,250 cc.) and the solution obtained is concentrated to dryness under reduced pressure. 3-Hydroxy-2-(quinol-2-yl )isoindolin-l-one (6.2 g. ) , which melts at 175°C. , is thus obtained. 2-Phthalimidoquinoline can be prepared according to the method described by A.E. Porai-Koshits et coll, C.R. Acad. Sci. U.R.S.S. , 16, 453 (1937).
EXAMPLE 2 Following the procedure of Example 1 but starting with 2-( 7-chloroquinol-2-yl )-3-hydroxyisoindolin- 1-one (17.4 g. ) and l-chlorocarbonyl-4-methylpipera2ine (10.05 g. ) , 3-(4-methylpiperazin-l-yl ) carbonyloxy-2-( 7-chloroquinol-2-yl) isoindolin-l-one (15.6 g. ) , which melts at 174°C. , is obtained. 2-( 7-diloroquinol-2-yl )-3-hydroxyisoindolin- 1-one, which melts at 203°C. , can be prepared by the procedure described in Example 1 by reacting potassium borohydride with 7-chloro-2-phtIialimidoquinoline in an aqueous-methanolic medium at a temperature of about 20°C. 7-Chloro-2-phthalimidoquinoline can be prepared by heating a mixture of 2-amino-7-chloroquinoline (18.1 g.) and phthalic anhydride (14.9 g. ) in diphenyl ether (330 cc. ) at the reflux temperature for 15 minutes. After cooling to 60°C. , diisopropyl ether (330 cc.) is added to the reaction mixture. The product which crystallises is filtered off and then washed with diisopropyl ether (150 cc). After drying, 7-chloro-2-phthalimido-quinoline (28.2 g. ) , which melts at 227°C. , is obtained. 2~Andno-7--chloroquinoline can be prepared by heating a mixture of 2 , 7-dichloroquinoline (36.7 g. ) and 16N ammonia solution (700 cc.) in an autoclave at 125°C« for 25 hours. After cooling, an insoluble product is filtered off and then washed with water (120 cc). After drying, a product (34 g. ) , which melts at about 115-120°C. , is obtained. On recrystallisation from benzene (150 cc. ) , 2-amino-7-chloroquinoline (10 g. ) , which melts at 175°C. , is obtained. 2 , 7-Dichloroquinoline can be prepared according to the method described by R.3. Lutz et coll, J. Am. Chem. Soc. , 68, 1322 (1946).
EXAMPLE 3 A suspension of 3-hydroxy-2-( 7-nitroquinol-2-yl)isoindolin-i-one (7.2 g. ) in anhydrous dimethyl-formamide (70 cc.) is added to a suspension of sodium hydride (50% dispersion in mineral oil) (1.2 g.) in anhydrous dimethylformamide (90 cc), whilst keeping the temperature at about 20°C. When the evolution of gas has ceased, a solution of l-chlorocarbonyl-4-methyl-piperazine (4 g. ) in anhydrous dimethylformamide (25 cc.) is added. The reaction mixture is stirred for a further 3 hours after the end of the addition and is then poured into water (1,075 cc). The product which crystallises is filtered off and then washed twice with water (total 60 cc). After drying, a product (8.6 g. ) , melting at about 228-230°C. , is obtained and is dissolved in methylene chloride (170 cc. ) . The solution obtained is filtered through silica gel (170 g. ) contained in a column 3.6 era. in diameter. Elution is then carried out with pure methylene chloride (350 cc.),a mixture of methylene chloride and methanol (99-1 by volume; 680 cc. ) and a mixture of methylene chloride and methanol (98-2 by volume; 680 cc). All these eluates are discarded.
Further elution is carried out with a mixture of methylene chloride and methanol (98-2 by volume; 680 cc. ) and the solution obtained is concentrated to dryness under reduced pressure. After recrystallisation of the residue obtained from a mixture of acetonitrile and dimethylformamide (50-50 by volume; 80 cc), 3-( 4-methylpiperazin-l-yl) carbon loxy-2-( 7-nitroquinol-2-yl)isoindolin-l-one (5 g. ) , which melts at 240°C, is obtained. 3-Kydroxy-2-( 7-nitroquinol-2-yl )isoindolin- 1-one, which melts at 264°G. , can be prepared by reacting potassium borohydride with 7-nitro-2-phthalimidoquinoline in an aqueous-methanolic medium at a temperature of about 20°c. 7-Nitro—2-phthalimidoquinoline, which melts at 295-297°C. , can be prepared by reacting phthalic anhydride with 2-amino-7-nitroquinoline in diphenyl ether at a temperature of about 220°C. 2-Amino-7-nitrpquinoline can be prepared by heating 2-chloro-7-nitroquinoline (11.4 g. ) and ammonia solution (d = 0.89; 220 cc. ) in an autoclave for 24 hours at a temperature of about 130°C. After cooling and releasing the gas, the insoluble product is filtered off and then washed three times with water (total 60 cc).
After drying, 2-amino-7-nitroquinoline (9.8 g. ) , which melts at 226-228°C , is obtained* 2-Chloro-7-nitroquinoline can be prepared by heating a solution of 1-methyl--7-nitrocarbostyril (39.1 g.) and phosphorus pentachloride (56.3 g) in phosphorus oxychloride (l92.cc. ) at the re ux temperature for 5 hours. After cooling, the reaction mixture is poured onto crushed ice (3 kg). The insoluble product is filtered off* washed five times with water (total 650 cc.) and then dried in air. On rectystallisation from carbon tetrachloride (700 cc), 2-chloro-7-nitroquinoline (29.4 g. )» which melts at 138°C , is obtained. 1-Methyl-7-nitrocarboBtyril can be prepared according to the method described by H* Decker, J. Prakt, Chem., 6£, 85 (1901 ).
Example 4 Following the procedure of Example 1 but starting with 3-hydroxy-2-( -methoxyquino 1-2- 1)-isoindolin- 1-one (7.55 g) and l-chlorocaronyl-4-methylpiperazine (5.0 g)# 3-(4-methylpiperazin-1-yl)-car'bonylozy-2-(7-methoxyquinol-2-yl)isoindolin-1-one (9.7 g), which melts at 195°C , is obtained after recrystallisation from acetonitrile (400 cc.)» 3-Hyciroxy-2-( 7-methoxyquinol-2-yl)i80indolin-1-one, whioh melts at 168°C can be prepared by reacting potassium borohydride with 7-methoxy-2-phtha-limidoquinoline in a mixture of dioxan and water (95-5 by volume) at a o temperature of about 20 C. 0 7-Methoxy-2-phthalimidoquinollne, which melts at 208 c, can be prepared by reacting phthallc anhydride with 2-amino-7-methoxyquinoline in diphenyl ether at a temperature of about 240°C . 2H¾mino-7-methoxyquinoline, which melts at 85°C, can be prepared by reacting ammonia with 2-chloro-7-methoxyquinoline in the presence of cuprous chloride at a temperature of about 135°C. 2-Chloro--7-methoxyquinoline, which melts at 98-100°C. , can be prepared by reacting phosphorus pentachloride with 7-methoiiy-carbostyril in reflud.ng phosphorus oxychloride. 7-Methoxy-carbostyril can be prepared according to the method described by F. Effenberger and . Hartmann, Chem. Ber., 102, 3260 (1969).
Following the procedure of Example 1 but starting with 3-hydroxy-2-(7-methylquinol-2-yl)-isoindolin-l-one (5.8 g. ) and l-chlorocarbonyl-4-methylpiperazine (3.6 g. ) , 3-(4-methylpiperazin-l-yl)-carbonyloxy-2-( 7-methylquinol-2-yl )isoindolin-l-one (6.95 g. ) , which melts at 162-163°C. , is obtained after recrystallisation from acetonitrile (50 cc). 3-Hydroxy-2-( 7-methylquinol-2-yl) isoindolin-l-one, which melts at 175°C. , can be prepared by reacting potassium borohydride with 7-methyl-2-phthalimidoquinoline in a mixture of dioxan and water (95-5 by volume) at a temperature of about 20°C. 7-lIethyl-2-phthalimidoquinoline, which melts at 197°C. , can be prepared by reacting phthalic anhydride with 2-amino-7-methylquinoline in diphenyl ether at a temperature of about 205 °C. 2-Amino-7-metiyiquinoline, which melts at 134-135 °C. , can be prepared by reacting ammonia with 2-chloro-7-methylquinoline in the presence of cuprous chloride at a temperature of about 120°C. 2-Chloro-7-methylquinoline can be prepared according to the method described by J.D. Capps, J. Am. Chem. Soc, 69,179 (1947).
EXAMPL2 T £ A solution of 3-(4-methylpiperazin-l-yl)- carbonyloxy¾-2-( 7-chloroquinol-2-yl )isoindolin-l-one (6 g. ) in chloroform (42 cc. ) is added to a suspension of p-nitroperbenzoic acid (3 g. ) in chloroform (150 cc). The reaction mixture is then stirred for 3 hours at a temperature of about 25°C. An aqueous 4N sodium hydroxide solution (10 cc.) is then added and the mixture is stirred for 10 minutes. Anhydrous sodium sulphate (150 g. ) is then added, stirring is continued for 10 minutes and then the sodium sulphate is filtered off and washed three times with chloroform (total 150 cc), The solution obtained is concentrated to dryness under reduced pressure and the residue obtained is dissolved in a mixture of acetone and water (80-20 by volume; 100 cc). The solution obtained ia treated with decolourising charcoal and is filtered, and then distilled water (200 cc. ) is added to it. The product which crystallises is filtered off and washed with distilled water (20 cc), After drying, 4-[2-( 7-chloroquinol-2-yl)-l-oxo-isoindolin-3-yl]-oxycarbonyl-l-methylpiperazine 1-oxide monohydrate (6.6 g. ) is obtained, which undergoes transformation at about 170°C. and then melts at 240°C.
Hie present invention includes within its scope pharmaceutical compositions comprising, as active ingredient, at least one of the isoindoline derivatives of general formula I, or a non-toxic acid addition salt thereof, in association with a pharmaceutical carrier or coating* The invention includes especially such preparations raade up for oral, parenteral or rectal administration.
Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water or liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting, emulsifying and suspending agents, and sweetening, flavouring and aromatizing agents. The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing the active substance with or without the addition of diluents or excipients.
Preparations according to the invention for parenteral administration include sterile aqueous or , non-aqueous solutions, suspensions or emulsions.
Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilizing agents, by irradiation, or by heating, They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Conipositions for rectal administration are suppositories which contain, in addition to the active substance, excipients such as cacao butter or a suitable wax base.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. The dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. In human therapy the compositions when administered orally to an adult should generally give doses between 50 mg. and 500 mg. of active substance per day. In general the physician will decide the posology considered appropriate, taking into account the age and weight and other factors intrinsic to the patient being treated.
The following Ex mple illustrate pharmaceutical compositions according to the invention.
EXAMPLE T ?~ Ta lets containing 25 mg. of active product and having the following composition are prepared in accordance with the usual techniques 3-(4-methylpiperazin-l-yl ) carbonyloxy-2-( 7-chloroquinol-2-yl)isoindolin-l-one 0.025 g. starch 0.090 g. precipitated silica 0.030 g. magnesium stearate 0.005 g.

Claims (24)

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1. Isoindollne derivatives of the general formula: wherein Y represents a hydrogen or halogen atom, an alkyl or alkoxy radical containing 1 to 4 carbon atoms or a nitro radical and n represents zero or 1 , and acid additions salts thereof.
2. Isoindollne compounds according to claim 1 wherein n represents zero.
3. Isoindollne compounds according to claim 1 and 2 wherein Y represents a. chlorine atom or a methyl, methoxy or nitro group.
4. Isoindollne compounds accordin to any one of claims 1 to 3 wherein the quinolyl radical is attached through the 2-position to the isoindollne nucleus.
5. 3- (4-Methylpiperazin-l-yl)carbonyloxy-2- (quinol-2-yl) isoindolin-l-one.
6. 3- (4-Methylpiperazin-l-yl)carbonyloxy-2- (7-chioroquinol-2-yl) isoindolin-l-one.
7. 3- (4-Methylpiperazin-l-yl)carbonyloxy-2- <7-nitroquinol-2-yl) isoindolin-l-one.
8. 3- (4-Methylpiperazin-l-yl)carbonyloxy-2- (7-methoxyquinol-2-yl) isoindolin-l-one.
9. 3-(4-Methylpiperzin-l-yl)carbonyloxy-2-(7~ mefchylguinol-2-yl) isoindolin-l-one.
10. 4-12- (7-Chloroquinol-2-yl)-1-oxo-isoindolin- 3-yl)-oxycarbonyl-l-methylpiperazine 1-oxide.
11. Acid addition salts of an isoindoline derivative claimed in any one of claims 1 to 10.
12. Process for the preparation of isoindoline derivatives as claimed in claim 1, wherein n represents zero, which comprises reacting l-chloro¾arbonyl-4-methyl- piperazine with an alkali metal salt of an isoindoline derivative of the general formula: L I IS wherein the various symbols are as defined in claim 1·
13. Process according to claim 15 in which the reaction is carried out in an anhydrous organic solvent at a temperature below S0°C.
14. . Process for the preparation of isoindoline derivatives as claimed in claim 1, wherein n represents zero, which comprises reacting 1-methyl-piperazine with a mixed carbonate of the general formula: wherein Y is as defined in claim 1, and Ar represents a phenyl radical optionally substituted by an alkyl radical containing 1 to 4 carbon atoms.
15. Process according to claim 14 in which the reaction is carried out in an organic solvent and at a temperature between 10° and 35°C.
16. Process for the preparation of isoindoline derivatives as claimed in claim 1, wherein n represents 1, which comprises oxidising a corresponding compound of the general ormula specified in claim 1 wherein n is zero by methods known per se for the N-oxidation of the piperazine nucleus*
17. Process according to claim 16 in which the oxidation is carried out by means of a peracid in an organic solvent and at a temperature of about 20°C.
18. Process according to any one of claims 12 to 17 followed by the step of converting by methods known per se an isoindoline derivative thus obtained into an acid addition salt.
19. ¾-?. Process for the preparation of isoindoline derivatives of the general formula specified in claim 1 substantially as described in Example 1 or 2.
20. ϋ» Process for the preparation of isoindoline derivatives of the general formula specified in claim 1 substantially as described in Example 6.
21. Process for the preparation of isoindoline derivatives of the general formula specified in claim 1 or substantially as described in Example 3, 4,/ 5
22. 2&- Isoindoline derivatives of the general formula specified in claim 1 and acid addition salts thereof when prepared by th process claimed in any one of claims ¾5 to ·24π- 12 to 21.
23. 25.. Pharmaceutical compositions which comprise, as active ingredient, at least one isoindoline derivative 10 as claimed in any one of claims 1 to i6-f or a non-toxic acid addition salt thereof, in association with a pharmaceutical carrier or coating.
24. S_T¾ Pharmaceutical compositions according to claim 2& substantially as hereinbefore described with especial reference to Example -θτ 7. 2θ
IL41259A 1972-01-10 1973-01-09 3-((4-methyl-1-piperazinyl carbonyl)oxy)-2-(2-quinolyl)-1-isoindoline derivatives,process for their preparation and pharmaceutical compositions containing the same IL41259A (en)

Applications Claiming Priority (2)

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FR7200650A FR2167217A1 (en) 1972-01-10 1972-01-10 Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants
FR7241272A FR2206936A2 (en) 1972-11-21 1972-11-21 Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants

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IL41259A true IL41259A (en) 1976-09-30

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FR2286642A2 (en) * 1974-03-14 1976-04-30 Rhone Poulenc Ind 2-(Naphthyridin-2-yl)-isoindolin-1-one derivs - contg. 3-(piperazin-1-yl-carbonyloxy) gp., used as tranquillisers and antidepressants
US3992382A (en) * 1973-06-15 1976-11-16 The Upjohn Company Quinolylaminobenzoylpiperazine-1-oxides
AR208414A1 (en) * 1974-11-07 1976-12-27 Rhone Poulenc Ind PROCEDURE TO OBTAIN NEW DERIVATIVES OF ((ACIL-4PIPERAZINIL-1) CARBONYLOXI-5 PYRROLINONE-2)
FR2322601A1 (en) * 1975-09-04 1977-04-01 Rhone Poulenc Ind Pyrrolidinone deriirrivs as tranquillizers - 1-Heterocyclyl-5(1-piperazinyl-carbonyloxy)-2(5H)-pyrrolidinone derivs prepd. from 5-aryloxycarbonyloxy cpds. and piperazine (OE060576)
FR2607503B1 (en) * 1986-12-02 1989-02-24 Rhone Poulenc Sante NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2005105061A2 (en) * 2004-04-14 2005-11-10 Indevus Pharmaceuticals, Inc. Transdermal patch

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US3466297A (en) * 1967-03-14 1969-09-09 American Home Prod 2-(2-aminophenyl)isoindolines
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IL41259A0 (en) 1973-03-30
JPS5610315B2 (en) 1981-03-06
CH554353A (en) 1974-09-30
FI55198C (en) 1979-06-11
AR197485A1 (en) 1974-04-15
YU35765B (en) 1981-06-30
NL178690C (en) 1986-05-01
CH554354A (en) 1974-09-30
PH9482A (en) 1976-01-08
US3884921A (en) 1975-05-20
NO136840C (en) 1977-11-16
GB1367589A (en) 1974-09-18
AT325622B (en) 1975-10-27
AT325626B (en) 1975-10-27
IE37088B1 (en) 1977-04-27
JPS4880577A (en) 1973-10-29
NL178690B (en) 1985-12-02
DE2301069A1 (en) 1973-07-19
LU66810A1 (en) 1973-07-18
BE793851A (en) 1973-07-10
DK138117B (en) 1978-07-17
NO136840B (en) 1977-08-08
OA04286A (en) 1979-12-31
DK138117C (en) 1979-01-15
CA991184A (en) 1976-06-15
NL7300024A (en) 1973-07-12
YU4073A (en) 1980-10-31
HU164822B (en) 1974-04-11
ATA18773A (en) 1975-01-15
IE37088L (en) 1973-07-10
DD102697A5 (en) 1973-12-20
DE2301069C2 (en) 1983-10-27
SE384510B (en) 1976-05-10
FI55198B (en) 1979-02-28

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